CN117956995A - Application of EZH2 inhibitor in preparation of medicines for treating T cell lymphoma - Google Patents
Application of EZH2 inhibitor in preparation of medicines for treating T cell lymphoma Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
Relates to an application of an EZH2 inhibitor in preparing a medicament for treating T cell lymphoma. In particular to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for treating T cell lymphoma.
Description
The present application claims priority from chinese patent application 2021110016631, whose filing date is 2021, 8, 30. The present application incorporates the entirety of the above-mentioned chinese patent application.
The present disclosure relates to an application of an EZH2 inhibitor in preparing a medicine for treating T cell lymphoma, and belongs to the field of medicines.
EZH2 (enhancer of zeste homolog 2) is a core component of histone methyltransferase PRC2 (polycombrepressive complex 2) that triggers and maintains the transcription repression state of chromosome by catalyzing the tri-methylation of lysine 27 at amino terminal end of histone H3 (H3K 27Me 3), and represses target gene expression. Most of the target genes have the effects of inhibiting cell proliferation and promoting cell differentiation, thereby playing an important role in the processes of maintaining embryo development and resisting cell aging.
Peripheral T Cell Lymphoma (PTCL), also known as mature T cell lymphoma, is a group of malignant proliferative diseases with obvious heterogeneity originating from mature T cells, often categorized as NK cell lymphomas and mature T cell lymphomas because NK cells behave immunologically and function similarly to T cells.
Currently, there is no standard treatment regimen for PTCL, and the first line treatment is commonly used as a CHOP or CHOP-like regimen with a 5-year survival rate of only about 30%. For recurrent or refractory PTCL (rrPTCL), clinical trials are recommended at home and abroad, and other I-level specialists recommend treatments including single new drugs and combined chemotherapy, but the traditional chemotherapy has unsatisfactory curative effects. The prior Sidamine and pramipexole are used for rrPTCL treatment in China, ORR is 27-52 percent, and PFS is 2.1-4.8 months. Patients who relapse or are refractory after treatment by the new medicine have no available treatment. In summary, traditional chemotherapy has not been shown to have optimal efficacy in relapsed refractory PTCL, histone Deacetylase (HDAC) inhibitors and folic acid inhibitors are used in batches for such patients, but the improvement in efficacy is limited. There is still a need to develop more new and effective drugs to improve prognosis in patients with refractory PTCL.
Disclosure of Invention
The present disclosure provides an application of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for treating T cell lymphoma,
In some embodiments, the T cell lymphoma described in the present disclosure is peripheral T cell lymphoma (mature T and NK cell lymphoma).
In some embodiments, the T cell lymphoma described in the present disclosure is angioimmunoblastic T cell lymphoma (AITL), anaplastic Large Cell Lymphoma (ALCL), peripheral T cell lymphoma-unspecified (PTCL-NOS), or NK/T cell lymphoma (NKTCL).
In some embodiments, the T cell lymphoma described in the present disclosure is angioimmunoblastic T cell lymphoma or peripheral T cell lymphoma-unspecific.
In some embodiments, the T cell lymphoma described in the present disclosure is angioimmunoblastic T cell lymphoma.
In some embodiments, the T cell lymphoma described in the present disclosure is peripheral T cell lymphoma-unspecified.
In some embodiments, the T cell lymphoma described in the present disclosure is relapsed/refractory peripheral T cell lymphoma.
In some embodiments, the T cell lymphoma described in the present disclosure is peripheral T cell lymphoma that has been subjected to first-line chemotherapy.
In some embodiments, the T cell lymphoma described in the present disclosure is peripheral T cell lymphoma that has been treated with at least one therapeutic agent selected from the group consisting of histone deacetylase inhibitors, inhibitors of folate metabolism, or anti-CD 30 mab.
In some embodiments, the T cell lymphoma described in the present disclosure is peripheral T cell lymphoma that has been treated with first-line chemotherapy and at least one therapeutic agent selected from the group consisting of a histone deacetylase inhibitor, a folic acid metabolism inhibitor, or an anti-CD 30 mab.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dose selected from the group consisting of 1mg to 800mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 2.5mg、5.0mg、7.5mg、10.0mg、12.5mg、15.0mg、17.5mg、20.0mg、22.5mg、25.0mg、27.5mg、30.0mg、32.5mg、35.0mg、37.5mg、40.0mg、42.5mg、45.0mg、47.5mg、50.0mg、52.5mg、55.0mg、57.5mg、60.0mg、62.5mg、65.0mg、67.5mg、70.0mg、72.5mg、75.0mg、77.5mg、80.0mg、82.5mg、85.0mg、87.5mg、90.0mg、92.5mg、95.0mg、97.5mg、100.0mg、102.5mg、105.0mg、107.5mg、110.0mg、112.5mg、115.0mg、117.5mg、120.0mg、122.5mg、125.0mg、127.5mg、130.0mg、132.5mg、135.0mg、137.5mg、140.0mg、142.5mg、145.0mg、147.5mg、150.0mg、152.5mg、155.0mg、157.5mg、160.0mg、162.5mg、165.0mg、167.5mg、170.0mg、172.5mg、175.0mg、177.5mg、180.0mg、182.5mg、185.0mg、187.5mg、190.0mg、192.5mg、195.0mg、197.5mg、200.0mg、202.5mg、205.0mg、207.5mg、210.0mg、212.5mg、215.0mg、217.5mg、220.0mg、222.5mg、225.0mg、227.5mg、230.0mg、232.5mg、235.0mg、237.5mg、240.0mg、242.5mg、245.0mg、247.5mg、250.0mg、252.5mg、255.0mg、 257.5mg、260.0mg、262.5mg、265.0mg、267.5mg、270.0mg、272.5mg、275.0mg、277.5mg、280.0mg、282.5mg、285.0mg、287.5mg、290.0mg、292.5mg、295.0mg、297.5mg、300.0mg、302.5mg、305.0mg、307.5mg、310.0mg、312.5mg、315.0mg、317.5mg、320.0mg、322.5mg、325.0mg、327.5mg、330.0mg、332.5mg、335.0mg、337.5mg、340.0mg、342.5mg、345.0mg、347.5mg、350.0mg、352.5mg、355.0mg、357.5mg、360.0mg、362.5mg、365.0mg、367.5mg、370.0mg、372.5mg、375.0mg、377.5mg、380.0mg、382.5mg、385.0mg、387.5mg、390.0mg、392.5mg、395.0mg、397.5mg、400.0mg、402.5mg、405.0mg、407.5mg、410.0mg、412.5mg、415.0mg、417.5mg、420.0mg、422.5mg、425.0mg、427.5mg、430.0mg、432.5mg、435.0mg、437.5mg、440.0mg、442.5mg、445.0mg、447.5mg、450.0mg、452.5mg、455.0mg、457.5mg、460.0mg、462.5mg、465.0mg、467.5mg、470.0mg、472.5mg、475.0mg、477.5mg、480.0mg、482.5mg、485.0mg、487.5mg、490.0mg、492.5mg、495.0mg、497.5mg、500.0mg、502.5mg、505.0mg、507.5mg、510.0mg、512.5mg、515.0mg、517.5mg、520.0mg、522.5mg、525.0mg、527.5mg、530.0mg、532.5mg、535.0mg、537.5mg、540.0mg、542.5mg、545.0mg、547.5mg、550.0mg、552.5mg、555.0mg、557.5mg、560.0mg、562.5mg、565.0mg、567.5mg、570.0mg、572.5mg、575.0mg、577.5mg、580.0mg、582.5mg、585.0mg、587.5mg、590.0mg、592.5mg、595.0mg、597.5mg、600.0mg、602.5mg、605.0mg、607.5mg、610.0mg、612.5mg、615.0mg、617.5mg、620.0mg、622.5mg、625.0mg、627.5mg、630.0mg、632.5mg、635.0mg、637.5mg、640.0mg、642.5mg、645.0mg、647.5mg、650.0mg、652.5mg、655.0mg、657.5mg、660.0mg、662.5mg、665.0mg、667.5mg、670.0mg、672.5mg、675.0mg、677.5mg、680.0mg、682.5mg、685.0mg、687.5mg、690.0mg、692.5mg、 695.0mg、697.5mg、700.0mg、702.5mg、705.0mg、707.5mg、710.0mg、712.5mg、715.0mg、717.5mg、720.0mg、722.5mg、725.0mg、727.5mg、730.0mg、732.5mg、735.0mg、737.5mg、740.0mg、742.5mg、745.0mg、747.5mg、750.0mg、752.5mg、755.0mg、757.5mg、760.0mg、762.5mg、765.0mg、767.5mg、770.0mg、772.5mg、775.0mg、777.5mg、780.0mg、782.5mg、785.0mg、787.5mg、790.0mg、792.5mg、795.0mg、797.5mg or 800.0mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg or 600mg, once a day or twice a day on a frequent basis.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 50mg, 100mg, 200mg, 300mg, 350mg, or 400mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 200mg, 300mg, or 350mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 200mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of 300mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of 350mg, at a frequency of once a day or twice a day.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 200mg, 300mg, or 350mg, at a frequency of twice daily.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 200mg, twice daily.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of 300mg, twice daily.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of 350mg, twice daily.
Another aspect of the present disclosure provides a method of treating T cell lymphoma comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect of the present disclosure, there is provided a method of treating T cell lymphoma by administering to a patient 1mg to 800mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, once a day or twice a day.
In some embodiments, the present disclosure provides methods of treating T cell lymphoma for 28 days with one dosing cycle.
Another aspect of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of T cell lymphoma.
The term "patient" as used in this disclosure means a human.
The acetylase inhibitors described in the present disclosure include, but are not limited to, cetadamine, belinostat or romidepsin; such folic acid metabolism inhibitors include, but are not limited to, pramipexole; the anti-CD 30 antibodies include, but are not limited to, velbutuximab.
Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated in particular in solid or liquid form for oral administration, or for topical administration.
The disclosure further provides the use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers in the manufacture of a medicament for the treatment of T cell lymphoma.
By "pharmaceutically acceptable carrier" as used in this disclosure is meant any type of non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary. Some examples of substances that may be pharmaceutically acceptable carriers are sugars, such as: lactose or cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate.
In alternative embodiments, the patient in the present disclosure is treated with first line chemotherapy and at least one neo-drug (cidamine, pralatrexed, velbutuximab), wherein:
-CD30 systemic ALCL, receiving treatment with velbutuximab;
-NKTCL: treatment with an asparaginase/peginase regimen;
-other subtypes: treatment with CHOP or CHOP-like regimens (including, but not limited to, CHOEP, bv+chp) was received.
The relapse is refractory, the disease progress occurs after the remission of the last line treatment, and the refractory is that the remission of the last treatment is not achieved.
ORR: the proportion of subjects who have reached CR or PR for optimal efficacy is defined from the start of the first dose to the onset of PD or the start of a subsequent new anti-tumor treatment, based on the first occurrence.
PFS: defined as the date of first appearance from the start of the first administration to the first record of PD or any cause of death. If the subject has not yet developed PD or die at the date of expiration of the data, the date of expiration is the date of the last efficacy assessment of the subject. If the subject did not receive a tumor evaluation, the expiration date is the first dose date and PFS continues for 1 day.
DoR: defined as the time from the first evaluation of CR or PR to the first evaluation of PD or any cause of death, based on the first appearance. If the subject has not yet developed PD or die at the date of expiration of the data, the date of end of the period is the date of the last efficacy assessment of the subject. Only subjects who achieved CR or PR.
Disease progression is defined as worsening of the subject's condition caused by the indication studied. Including imaging progression, test result progression, and progression of clinical symptoms and signs. The appearance of new lesions, or the progression of an original lesion, is considered to be disease progression. Life threatening due to symptoms and signs of disease progression, requiring hospitalization or prolonged hospitalization, or causing permanent or severe disability/insufficiency/affecting working ability, events of congenital abnormalities or birth defects are not reported as SAE. Death due to symptoms and signs of disease progression is reported as SAE.
An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.
The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.
Example 1, study of the Effect of Compounds of formula (I) on peripheral T cell lymphomas
1.1 Drugs: a compound of formula (I) (WO 2017084494 a), specification: 50 mg/tablet, 200 mg/tablet;
1.2 modes of administration: 350mg twice a day, 28 days being a cycle.
1.3 Group criteria, relapsed or refractory T-lymphocyte lymphomas.
The 350mg group co-administration group 24 patients with refractory PTCL, 16 of which received the sedaxane, were subjected to effect data analysis in terms of indistinguishable from the previous treatment and the previous treatment with sedaxane, as shown in table 1.
TABLE 1 Objective remission rates for different groups
24 PTCL groups with an overall ORR of 50%; of these, PTCL-NOS 9, AITL15, and both ORRs were 44.4% and 53.3%, respectively. 18 cases of ES set, ORR 66.7%; among them, PTCL-NOS 7 cases, AITL11 cases, and ORRs of both groups were 57.1% and 72.7%, respectively.
16 Of the 24 PTCL groups received persidan with an overall ORR of 56.3%; among these, PTCL-NOS 6 cases, AITL10 cases, and ORRs of the two groups were 66.7% and 50.0%, respectively. ES set 14 cases with ORR 64.3%; of these, PTCL-NOS 6, AITL8, and ORRs of the two groups were 66.7% and 62.5%, respectively.
Claims (6)
- The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of T cell lymphoma,
- The use according to claim 1, wherein the T-cell lymphoma is peripheral T-cell lymphoma (mature T-and NK-cell lymphoma), preferably angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, peripheral T-lymphoma-non-fingered or NK/T-cell lymphoma, most preferably angioimmunoblastic T-cell lymphoma or peripheral T-lymphoma-non-fingered.
- The use according to claim 2, wherein the peripheral T cell lymphoma is relapsed/refractory peripheral T cell lymphoma.
- The use according to claim 2, wherein the peripheral T cell lymphoma is treated with first-line chemotherapy and/or at least one peripheral T cell lymphoma selected from histone deacetylase inhibitors, folic acid metabolism inhibitors, or anti-CD 30 mab, preferably wherein the peripheral T cell lymphoma is treated with first-line chemotherapy or with first-line chemotherapy and at least one peripheral T cell lymphoma selected from histone deacetylase inhibitors, folic acid metabolism inhibitors, or anti-CD 30 mab.
- The use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dose selected from the group consisting of 1mg to 800mg, at a frequency of once a day or twice a day.
- The use according to claim 5, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount selected from 50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg or 600mg, once a day or twice a day; preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dose selected from 50mg, 100mg, 200mg, 300mg, 350mg or 400mg, at a frequency of once a day or twice a day; most preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from 200mg, 300mg or 350mg, at a frequency of once a day or twice a day.
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| CN2021110016631 | 2021-08-30 | ||
| CN202111001663 | 2021-08-30 | ||
| PCT/CN2022/115763 WO2023030299A1 (en) | 2021-08-30 | 2022-08-30 | Use of ezh2 inhibitor in preparation of drug for treating t-cell lymphoma |
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| EP (1) | EP4393490A1 (en) |
| JP (1) | JP2024530310A (en) |
| KR (1) | KR20240056564A (en) |
| CN (1) | CN117956995A (en) |
| AU (1) | AU2022340500A1 (en) |
| CA (1) | CA3230149A1 (en) |
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| MX (1) | MX2024002538A (en) |
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| EP3323820B1 (en) * | 2011-02-28 | 2023-05-10 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
| AU2016357900B2 (en) | 2015-11-19 | 2020-09-17 | Jiangsu Hengrui Medicine Co., Ltd. | Benzofuran derivative, preparation method thereof and use thereof in medicine |
| CN110179796B (en) * | 2018-02-23 | 2023-01-24 | 江苏恒瑞医药股份有限公司 | Benzofuran derivative composition and preparation method thereof |
| CN113767096B (en) * | 2019-05-10 | 2022-11-22 | 江苏恒瑞医药股份有限公司 | Preparation method of 6-substituted aminobenzofuran compound |
| WO2021063340A1 (en) * | 2019-09-30 | 2021-04-08 | 江苏恒瑞医药股份有限公司 | Use of ezh2 inhibitor in combination with immune checkpoint inhibitor and tyrosine kinase inhibitor in preparation of medication for treating tumor |
| WO2021063331A1 (en) * | 2019-09-30 | 2021-04-08 | 江苏恒瑞医药股份有限公司 | USE OF COMBINATION OF EZH2 INHIBITOR AND TGF-β RECEPTOR-CONTAINING FUSION PROTEIN IN PREPARATION OF DRUGS FOR TREATING TUMORS |
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| MX2024002538A (en) | 2024-03-19 |
| AU2022340500A1 (en) | 2024-04-11 |
| KR20240056564A (en) | 2024-04-30 |
| IL311097A (en) | 2024-04-01 |
| PE20240881A1 (en) | 2024-04-24 |
| TW202327597A (en) | 2023-07-16 |
| WO2023030299A1 (en) | 2023-03-09 |
| EP4393490A1 (en) | 2024-07-03 |
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